Interleukin-1 is a cytokine having a broad spectrum of biological activities (for reviews, see e.g., Dinarello, C. A. and Wolff, S. M. (1993) New Engl. J. Med. 328:106-113; and Dinarello, C. A. (1993) Trends in Pharmacol. Sci. 14:155-159). IL-1 consists of two structurally related polypeptides, interleukin-1.alpha. (IL-1.alpha.) and interleukin-1.beta. (IL-1.beta.). The two forms of IL-1 are encoded by different genes and have only 27-33% amino acid identity but they interact with the same receptor and have similar activities. Included among the biological functions attributed to IL-1 are induction of fever, sleep, anorexia and hypotension. IL-1 is also involved in the pathophysiology of inflammatory and autoimmune diseases, including rheumatoid arthritis, septic shock, inflammatory bowel disease and insulin dependent diabetes mellitus. IL-1.alpha. has been specifically implicated in the pathophysiology of psoriasis. IL-1 is also thought to play a role in immune responses to infectious agents and in the pathogenesis of myeloid leukemias.
IL-1.alpha. and IL-1.beta. are both synthesized as approximately 31 kDa precursor molecules that are subsequently processed to a mature form of approximately 17 kDa. IL-1.alpha. and IL-1.beta. differ in that the precursor form of IL-1.alpha. (preIL-IL-1.alpha. ) is biologically active and most of the mature IL-1.alpha. (matIL-1.alpha.) remains cell-associated, whereas the precursor form of IL-1.beta. (preIL-1.beta.) must be cleaved to its mature form to become active and the mature form of IL-1.beta. (matIL-1.beta.) is secreted from the cell. Only certain cell types process preIL-1.beta. and secrete matIL-1.beta.. Monocytes and macrophages are the most efficient producers and secretors of IL-1.beta., which is the most abundant form of IL-1 produced upon activation of these cell types.
An intracellular enzyme that cleaves preIL-1.beta. to matIL-1.beta. has been identified and termed interleukin-1.beta. converting enzyme (ICE) (Thornberry et al. (1992) Nature 356:768-774; Ceretti, D. P. et al. (1992) Science 256:97-100). ICE is a cysteine protease that cleaves the inactive form of IL-1.beta. between residues Asp.sup.116 and Ala.sup.117 to release the active 17 kDa form. ICE has not previously been implicated in the processing or secretion of IL-1.alpha.. Moreover, since other proteases, such as elastase and cathepsin G, can cleave preIL-1.beta. in vitro to yield matIL-1.beta. (see e.g., Black, R. A. et al. (1988) J. Biol. Chem. 263:9437-9442; and Hazuda, D. J. et al. (1990) J. Biol. Chem, 265:6318-6322), it is not known whether ICE is the primary or exclusive protease responsible for generation of bioactive IL-1.beta. in vivo.
In addition to cleaving IL-1.beta., there is evidence that ICE may be involved in apoptosis or programmed cell death. First, overexpression of ICE in a rat fibroblast cell line caused apoptosis. This apoptosis could be blocked either by the product of the bcl-2 gene, a mammalian oncogene that can prevent programmed cell death, or by the product of the cowpox virus crmA gene, which encodes a specific inhibitor of ICE (Yuan, J. et al. (1993) Cell 75:641-652; Ray, C. A. et al. (1992) Cell 69:597-604; Miura, M. et al. (1993) Cell 75:653-660). Moreover, microinjection of the ICE inhibitor crmA into chicken dorsal root ganglion neurons prevented cell death induced by nerve growth factor deprivation (Gagliardini, V. et al. (1994) Science 263:826). These observations suggest that ICE may have more widespread biological functions than simply cleaving preIL-1.beta. to matIL-.beta.. This further suggests that an ICE gene mutation could have seriously deleterious effects that would prevent normal biological development and viability.
Because of the apparently harmful role of IL-1 in many disease conditions, therapeutic strategies aimed at reducing the production or action of IL-1 have been proposed. One approach by which to inhibit matIL-1.beta. production and secretion is to block the activity of ICE with a specific ICE inhibitor. To identify ICE inhibitors and evaluate their efficacy, standard control animals and cells against which the activity of ICE inhibitors can be assessed are needed. Additionally, there is a need for model systems in which inhibitors of human ICE can be screened, either in vitro or in vivo. Moreover, while IL-1 has been implicated in the pathology of a number of diseases, the scope of disease conditions in which IL-1 is involved is not fully determined. Accordingly, model systems in which to assess the involvement of IL-1.alpha. and/or .beta. in disease states are needed to thereby identify disease conditions which may be treatable by ICE inhibitors.